Project Summary The work described in this proposal investigates the potential of exosomes harvested from cow's milk to be used as oral delivery vehicles for drugs that currently require infusion therapy. Our central hypothesis is that milk exosomes utilize the FcRn receptor that is constitutively expressed throughout life in humans. In addition, previous studies have documented that bovine IgG cross-reacts with human FcRn, and clinical trials have documented the presence of bovine miRNAs in the blood of patients who consumed milk. Although the FcRn receptor has been shown to facilitate the uptake of Fc-targeted nanoparticles across the gastrointestinal epithelium, the ability of exosomes to exploit this pathway has yet to be considered or investigated. Our preliminary data suggest that the oral bioavailability of exosome cargo exceeds 10%, and that uptake is greatly reduced if free bovine IgG is co-administered with milk exosomes; consistent with FcRn-mediated absorption. Previous studies have suggested that exosomes are transcytosed across the gastrointestinal epithelium as intact particles, and our results demonstrate that orally- administered, iRGD-targeted exosomes significantly enhance tumor delivery. In addition to the practical application of reducing the need for infusion therapy, the proposed experiments explore the mechanism by which transcytosis across the gastrointestinal epithelium is accomplished, and strives to identify unknown factors that have been proposed to contribute to this process.